Tracheal loss is a devastating condition and the trachea remains one of the remaining vital organs for which there is no adequate substitute. Attempts at engineering tracheal transplants from either synthetic constructs or decellularized tracheal scaffolds have met with limited success including long and complication-filled secondary healing and catastrophic tracheal luminal collapse. This proposal will investigate newly identified signaling pathways and the role that they play in limiting cellular and tissue regeneration, engraftment and tracheal angiogenesis. Knowledge gained from experiments in our unique murine model of orthotopic tracheal transplant will be translated into generating a functional shovel-ready human trachea.